Cognitive dysfunction is common in multiple sclerosis (MS). However, the relationship between white matter (WM) damage and cognition remains insufficiently clear. This study investigates the extent and severity of WM diffusion abnormalities in MS patients and relations with cognition. Diffusion tensor imaging scans were obtained in 131 MS patients (88 women, 6 years postdiagnosis) and 49 age-matched controls (29 women). Patient groups were equal in terms of disease duration, disability, and WM lesion volume. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were compared between groups. Post hoc analyses calculated the spatial extent and severity of diffusion abnormalities to relate these to cognitive performance. In controls, 31% of WM voxels showed higher FA in men; therefore, all patient analyses were within-sex. The extent of diffusion changes was higher in male patients than in female patients for all parameters (FA: 24% in women, 53% in men), as was the severity of changes (FA: Z = −0.18 in women, Z = −0.41 in men). Especially the extent of FA abnormalities was strongly related to cognitive performance in all patients (r = −0.42, P < 0.0001). Regionally, thalamic decreases in FA were especially correlated with cognitive performance. Cognitively impaired patients showed greater extent and severity on all diffusion parameters compared to cognitively preserved patients. The WM of male patients was both more extensively and also more severely affected than that of female patients. The extent of WM FA changes, especially in the thalamus, was associated with cognitive performance in this cohort of early MS patients. Hum Brain Mapp 35:2348–2358, 2014. © 2013 Wiley Periodicals, Inc.